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1.  Lamin B1 overexpression increases nuclear rigidity in autosomal dominant leukodystrophy fibroblasts 
The FASEB Journal  2014;28(9):3906-3918.
The architecture and structural mechanics of the cell nucleus are defined by the nuclear lamina, which is formed by A- and B-type lamins. Recently, gene duplication and protein overexpression of lamin B1 (LB1) have been reported in pedigrees with autosomal dominant leukodystrophy (ADLD). However, how the overexpression of LB1 affects nuclear mechanics and function and how it may result in pathology remain unexplored. Here, we report that in primary human skin fibroblasts derived from ADLD patients, LB1, but not other lamins, is overexpressed at the nuclear lamina and specifically enhances nuclear stiffness. Transient transfection of LB1 in HEK293 and neuronal N2a cells mimics the mechanical phenotype of ADLD nuclei. Notably, in ADLD fibroblasts, reducing LB1 protein levels by shRNA knockdown restores elasticity values to those indistinguishable from control fibroblasts. Moreover, isolated nuclei from ADLD fibroblasts display a reduced nuclear ion channel open probability on voltage-step application, suggesting that biophysical changes induced by LB1 overexpression may alter nuclear signaling cascades in somatic cells. Overall, the overexpression of LB1 in ADLD cells alters nuclear mechanics and is linked to changes in nuclear signaling, which could help explain the pathogenesis of this disease.—Ferrera, D., Canale, C., Marotta, R., Mazzaro, N., Gritti, M., Mazzanti, M., Capellari, S., Cortelli, P., Gasparini, L. Lamin B1 overexpression increases nuclear rigidity in autosomal dominant leukodystrophy fibroblasts.
doi:10.1096/fj.13-247635
PMCID: PMC4139899  PMID: 24858279
ADLD; nuclear lamina; atomic force microscopy; human fibroblasts; nucleus
2.  Analysis of LMNB1 duplications in Autosomal dominant Leukodystrophy Provides Insights into Duplication Mechanisms and allele specific Expression 
Human mutation  2013;34(8):1160-1171.
Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intra-chromosomal events. The duplication junction sequences indicated that non-homologous end joining (NHEJ) or replication-based mechanisms such fork stalling and template switching (FoSTeS) or microhomology mediated break induced repair (MMBIR) are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele specific LMNB1 expression levels.
doi:10.1002/humu.22348
PMCID: PMC3714349  PMID: 23649844
Lamin B1; Leukodystrophy; ADLD; Duplication Alu; NHEJ; FoSTeS; MMBIR
3.  Efficacy of early vs. late use of frovatriptan combined with dexketoprofen vs. frovatriptan alone in the acute treatment of migraine attacks with or without aura 
Neurological Sciences  2014;35(Suppl 1):107-113.
Early triptan use after headache onset may help improve the efficacy of acute migraine treatment. This may be particularly the case when triptan therapy is combined with a nonsteroidal anti-inflammatory drug (NSAID). The objective of this is to assess whether the combination of frovatriptan 2.5 mg + dexketoprofen 25 or 37.5 mg (FroDex25 and FroDex37.5) is superior to frovatriptan 2.5 mg alone (Frova) in the acute treatment of migraine attacks in patients who took the drug within 30 min from the onset of pain (early use) or after (late use). A total of 314 subjects with a history of migraine with or without aura were randomized into a double-blind, multicenter, parallel group, pilot study to Frova, FroDex25 or FroDex37.5 and were required to treat at least one migraine attack. In the present post hoc analysis, traditional migraine endpoints were compared across study drugs for subgroups of the 279 patients of the full analysis set according to early (n = 172) or late (n = 107) drug use. The proportion of patients pain free at 2 h in the early drug use subgroup was 33 % with Frova, 50 % with FroDex25 and 51 % with FroDex37.5 mg (p = NS combinations vs. monotherapy), while in the late drug use subgroup was 22, 51 and 50 % (p < 0.05 FroDex25 and FroDex37.5 vs. Frova), respectively. Pain-free episodes at 4 h were 54 % for early and 34 % for late use of Frova, 71 and 57 % with FroDex25 and 74 and 68 % with FroDex37.5 (p < 0.05 for early and p < 0.01 for late use vs. Frova). The proportion of sustained pain free at 24 h was 26 % under Frova, 43 % under FroDex25 mg and 40 % under FroDex37.5 mg (p = NS FroDex25 or 37.5 vs. Frova) in the early drug intake subgroup, while it was 19 % under Frova, 43 % under FroDex25 mg and 45 % under FroDex37.5 mg (p < 0.05 FroDex25 and FroDex37.5 vs. Frova) in the late drug intake subgroup. Risk of relapse at 48 h was similar (p = NS) among study drug groups (Frova: 25 %, FroDex25: 21 %, and FroDex37.5: 37 %) for the early as well as for the late drug use subgroup (14, 42 and 32 %). FroDex was found to be more effective than Frova taken either early or late. The intrinsic pharmacokinetic properties of the two single drug components made FroDex combination particularly effective within the 2–48-h window from the onset of the acute migraine attack. The efficacy does not seem to be influenced by the time of drug use relative to the onset of headache.
doi:10.1007/s10072-014-1751-3
PMCID: PMC4035546  PMID: 24867846
Migraine; Frovatriptan; Dexketoprofen; Early intake; Late intake
4.  Cognitive Function in Peripheral Autonomic Disorders 
PLoS ONE  2014;9(1):e85020.
Objective
aims of the current study were 1) to evaluate global cognitive function in patients with autonomic failure (AF) of peripheral origin and 2) to investigate the effect of a documented fall in blood pressure (BP) fulfilling the criteria for orthostatic hypotension (OH) on cognitive performances.
Methods
we assessed 12 consecutive patients (10 males, 68±7 years old) with pure AF (PAF) or autoimmune autonomic neuropathy (AAN) and 12 age- and gender-matched controls. All patients had no clinical signs of central nervous system involvement and normal brain CT/MRI scan. Cognitive function was assessed on two consecutive days in 3 conditions: on day 1, while sitting, by means of a comprehensive battery of neuropsychological tests; on day 2, while tilted (HUT) and during supine rest (supine) in a randomized manner. BP and heart rate (HR) were continuously recorded non-invasively for the whole duration of the examination.
Results
patients with PAF or AAN displayed a preserved global cognitive function while sitting. However, compared to supine assessment, during HUT patients scored significantly worse during the Trail Making Test A and B, Barrage test, Analogies test, Immediate Visual Memory, Span Forward and Span Backward test. Pathological scores, with regard to Italian normative range values, were observed only during HUT in the Barrage test and in the Analogies test in 3 and 6 patients respectively. On the contrary, in healthy controls, results to neuropsychological tests were not significantly different, during HUT compared to supine rest.
Conclusions
these data demonstrate that patients with PAF and AAN present a normal sitting global cognitive evaluation. However, their executive functions worsen significantly during the orthostatic challenge, possibly because of transient frontal lobes hypoperfusion.
doi:10.1371/journal.pone.0085020
PMCID: PMC3894940  PMID: 24465471
5.  Dopaminergic Neuronal Imaging in Genetic Parkinson's Disease: Insights into Pathogenesis 
PLoS ONE  2013;8(7):e69190.
Objectives
To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease.
Methods
A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case. The right:left asymmetry index and striatal asymmetry index was calculated.
Results
Scans were available from 37 cases of monogenetic Parkinson's disease (7 glucocerebrosidase (GBA) mutations, 8 alpha-synuclein, 3 LRRK2, 7 PINK1, 12 Parkin). The asymmetry of radioligand uptake for Parkinson's disease with GBA or LRRK2 mutations was greater than that for Parkinson's disease with alpha synuclein, PINK1 or Parkin mutations.
Conclusions
The asymmetry of radioligand uptake in Parkinsons disease associated with GBA or LRRK2 mutations suggests that interactions with additional genetic or environmental factors may be associated with dopaminergic neuronal loss.
doi:10.1371/journal.pone.0069190
PMCID: PMC3720622  PMID: 23935950
6.  Personality traits in chronic daily headache patients with and without psychiatric comorbidity: an observational study in a tertiary care headache center 
Background
Previous studies suggest that patients with Chronic Daily Headache (CDH) have higher levels of anxiety and depressive disorders than patients with episodic migraine or tension-type headache. However, no study has considered the presence of psychiatric comorbidity in the analysis of personality traits. The aim of this study is to investigate the prevalence of psychiatric comorbidity and specific personality traits in CDH patients, exploring if specific personality traits are associated to headache itself or to the psychiatric comorbidity associated with headache.
Methods
An observational, cross-sectional study. Ninety-four CDH patients with and without medication overuse were included in the study and assessed by clinical psychiatric interview and Mini International Neuropsychiatric Interview (M.I.N.I.) as diagnostic tools. Minnesota Multiphasic Personality Inventory-2 (MMPI-2), Hamilton Depression Rating Scale (HAM-D) were afterwards administered. Patients with and without psychiatric comorbidity were compared. Further analyses were made by splitting the whole group according to the headache diagnosis and the presence or not of medication overuse.
Results
Psychiatric comorbidity was detected in 44 patients (46.8%) (group A) and was absent in the remaining 50 patients (53.2%) (group B). Mood and anxiety disorders were the most frequently diagnosed (43.6%).
In the overall group, mean scores of MMPI-2 showed a high level in the so-called neurotic triad; in particular the mean score in the Hypochondriasis subscale was in the pathologic area (73.55 ± 13.59), while Depression and Hysteria scores were moderate but not severe (62.53 and 61.61, respectively). In content scales, score in Health Concern was also high (66.73).
Group A presented higher scores compared to Group B in the following MMPI-2 subscales: Hypochondriasis (p = .036), Depression (p = .032), Hysteria (p < .0001), Hypomania (p = .030). Group B had a high score only in the Hypochondriasis subscale. No significant differences were found between chronic migraine (CM)-probable CM (pCM) plus probable medication overuse headache (pMOH) and chronic tension-type headache (CTTH)-probable CTTH (pCTTH) plus pMOH patients or between patients with and without drug overuse.
Conclusions
The so-called “Neurotic Profile” reached clinical level only in CDH patients with psychiatric comorbidity while a high concern about their general health status was a common feature in all CDH patients.
doi:10.1186/1129-2377-14-22
PMCID: PMC3620450  PMID: 23566048
Chronic daily headache; Medication overuse headache; Psychiatric comorbidity; MMPI-2
7.  Cephalalgiaphobia as a feature of high-frequency migraine: a pilot study 
Background
Cephalalgiaphobia is the fear of having a headache attack during a pain-free period that may induce patients to use analgesic in the absence of pain to prevent headache and to improve their performances. This study aims at assessing if cephalalgiaphobia is related to migraine frequency or medication overuse, and if it is per se a predictor of increase in migraine frequency.
Methods
This is a pilot prospective cohort study on 126 consecutive migraineurs referred to a tertiary Headache Centre. A headache specialist collected data regarding migraine features, frequency and medications at baseline (T0) and 2 years later (T1). Cephalalgiaphobia was investigated at T0 and T1 through a score determined by a 4 items questionnaire.
Results
Moderate-high migraine frequency was associated with higher risk of cephalalgiaphobia (p < 0.001). Chronic migraineurs with medication overuse had higher score of cephalalgiaphobia than those without medication overuse (p < 0.001). Patients with increased migraine frequency between T0 and T1 had higher cephalalgiaphobia score (p < 0.001).
Conclusions
Cephalalgiaphobia may represent a high-frequency migraine feature and may play a role in chronicization. Therefore, it should be better investigated by clinicians and treated or prevented in order to reduce the risk of disability and the increase in migraine frequency.
doi:10.1186/1129-2377-14-49
PMCID: PMC3686604  PMID: 23759110
Migraine; Cephalalgiaphobia; Anxiety disorders; Chronic migraine
9.  Chronic migraine classification: current knowledge and future perspectives 
The Journal of Headache and Pain  2011;12(6):585-592.
In the field of so-called chronic daily headache, it is not easy for migraine that worsens progressively until it becomes daily or almost daily to find a precise and universally recognized place within the current international headache classification systems. In line with the 2006 revision of the second edition of the International Classification of Headache Disorders (ICHD-2R), the current prevailing opinion is that this headache type should be named chronic migraine (CM) and be characterized by the presence of at least 15 days of headache per month for at least 3 consecutive months, with headache having the same clinical features of migraine without aura for at least 8 of those 15 days. Based on much evidence, though, a CM with the above characteristics appears to be a heterogeneous entity and the obvious risk is that its definition may be extended to include a variety of different clinical entities. A proposal is advanced to consider CM a subtype of migraine without aura that is characterized by a high frequency of attacks (10–20 days of headache per month for at least 3 months) and is distinct from transformed migraine (TM), which in turn should be included in the classification as a complication of migraine. Therefore, CM should be removed from its current coding position in the ICHD-2 and be replaced by TM, which has more restrictive diagnostic criteria (at least 20 days of headache per month for at least 1 year, with no more than 5 consecutive days free of symptoms; same clinical features of migraine without aura for at least 10 of those 20 days).
doi:10.1007/s10194-011-0393-6
PMCID: PMC3208036  PMID: 22028184
Chronic migraine; Transformed migraine; Chronic daily headache; Chronic headache; Headache; Migraine
10.  Chronic migraine classification: current knowledge and future perspectives 
The Journal of Headache and Pain  2011;12(6):585-592.
In the field of so-called chronic daily headache, it is not easy for migraine that worsens progressively until it becomes daily or almost daily to find a precise and universally recognized place within the current international headache classification systems. In line with the 2006 revision of the second edition of the International Classification of Headache Disorders (ICHD-2R), the current prevailing opinion is that this headache type should be named chronic migraine (CM) and be characterized by the presence of at least 15 days of headache per month for at least 3 consecutive months, with headache having the same clinical features of migraine without aura for at least 8 of those 15 days. Based on much evidence, though, a CM with the above characteristics appears to be a heterogeneous entity and the obvious risk is that its definition may be extended to include a variety of different clinical entities. A proposal is advanced to consider CM a subtype of migraine without aura that is characterized by a high frequency of attacks (10–20 days of headache per month for at least 3 months) and is distinct from transformed migraine (TM), which in turn should be included in the classification as a complication of migraine. Therefore, CM should be removed from its current coding position in the ICHD-2 and be replaced by TM, which has more restrictive diagnostic criteria (at least 20 days of headache per month for at least 1 year, with no more than 5 consecutive days free of symptoms; same clinical features of migraine without aura for at least 10 of those 20 days).
doi:10.1007/s10194-011-0393-6
PMCID: PMC3208036  PMID: 22028184
Chronic migraine; Transformed migraine; Chronic daily headache; Chronic headache; Headache; Migraine
11.  Complex movement disorders at disease onset in childhood narcolepsy with cataplexy 
Brain  2011;134(12):3477-3489.
Narcolepsy with cataplexy is characterized by daytime sleepiness, cataplexy (sudden loss of bilateral muscle tone triggered by emotions), sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. Narcolepsy with cataplexy is most often associated with human leucocyte antigen-DQB1*0602 and is caused by the loss of hypocretin-producing neurons in the hypothalamus of likely autoimmune aetiology. Noting that children with narcolepsy often display complex abnormal motor behaviours close to disease onset that do not meet the classical definition of cataplexy, we systematically analysed motor features in 39 children with narcolepsy with cataplexy in comparison with 25 age- and sex-matched healthy controls. We found that patients with narcolepsy with cataplexy displayed a complex array of ‘negative’ (hypotonia) and ‘active’ (ranging from perioral movements to dyskinetic–dystonic movements or stereotypies) motor disturbances. ‘Active’ and ‘negative’ motor scores correlated positively with the presence of hypotonic features at neurological examination and negatively with disease duration, whereas ‘negative’ motor scores also correlated negatively with age at disease onset. These observations suggest that paediatric narcolepsy with cataplexy often co-occurs with a complex movement disorder at disease onset, a phenomenon that may vanish later in the course of the disease. Further studies are warranted to assess clinical course and whether the associated movement disorder is also caused by hypocretin deficiency or by additional neurochemical abnormalities.
doi:10.1093/brain/awr244
PMCID: PMC3235554  PMID: 21930661
hypotonia; movement disorder; narcolepsy with cataplexy; streptococcal infection; chorea
12.  Tribute to Pasquale Montagna, 1950–2010 
The Journal of Headache and Pain  2011;12(2):271-272.
doi:10.1007/s10194-011-0330-8
PMCID: PMC3072495  PMID: 21437712
13.  Tribute to Pasquale Montagna, 1950–2010 
The Journal of Headache and Pain  2011;12(2):271-272.
doi:10.1007/s10194-011-0330-8
PMCID: PMC3072495  PMID: 21437712
14.  Guidelines for the diagnosis and management of syncope (version 2009) 
Moya, Angel | Sutton, Richard | Ammirati, Fabrizio | Blanc, Jean-Jacques | Brignole, Michele | Dahm, Johannes B. | Deharo, Jean-Claude | Gajek, Jacek | Gjesdal, Knut | Krahn, Andrew | Massin, Martial | Pepi, Mauro | Pezawas, Thomas | Granell, Ricardo Ruiz | Sarasin, Francois | Ungar, Andrea | van Dijk, J. Gert | Walma, Edmond P. | Wieling, Wouter | Abe, Haruhiko | Benditt, David G. | Decker, Wyatt W. | Grubb, Blair P. | Kaufmann, Horacio | Morillo, Carlos | Olshansky, Brian | Parry, Steve W. | Sheldon, Robert | Shen, Win K. | Vahanian, Alec | Auricchio, Angelo | Bax, Jeroen | Ceconi, Claudio | Dean, Veronica | Filippatos, Gerasimos | Funck-Brentano, Christian | Hobbs, Richard | Kearney, Peter | McDonagh, Theresa | McGregor, Keith | Popescu, Bogdan A. | Reiner, Zeljko | Sechtem, Udo | Sirnes, Per Anton | Tendera, Michal | Vardas, Panos | Widimsky, Petr | Auricchio, Angelo | Acarturk, Esmeray | Andreotti, Felicita | Asteggiano, Riccardo | Bauersfeld, Urs | Bellou, Abdelouahab | Benetos, Athanase | Brandt, Johan | Chung, Mina K. | Cortelli, Pietro | Da Costa, Antoine | Extramiana, Fabrice | Ferro, José | Gorenek, Bulent | Hedman, Antti | Hirsch, Rafael | Kaliska, Gabriela | Kenny, Rose Anne | Kjeldsen, Keld Per | Lampert, Rachel | Mølgard, Henning | Paju, Rain | Puodziukynas, Aras | Raviele, Antonio | Roman, Pilar | Scherer, Martin | Schondorf, Ronald | Sicari, Rosa | Vanbrabant, Peter | Wolpert, Christian | Zamorano, Jose Luis
European Heart Journal  2009;30(21):2631-2671.
doi:10.1093/eurheartj/ehp298
PMCID: PMC3295536  PMID: 19713422
15.  Headache, anxiety and depressive disorders: the HADAS study 
The Journal of Headache and Pain  2010;11(2):141-150.
The objective of this paper was to assess prevalence and characteristics of anxiety and depression in migraine without aura and tension-type headache, either isolated or in combination. Although the association between headache and psychiatric disorders is undisputed, patients with migraine and/or tension-type headache have been frequently investigated in different settings and using different tests, which prevents meaningful comparisons. Psychiatric comorbidity was tested through structured interview and the MINI inventory in 158 adults with migraine without aura and in 216 persons with tension-type headache or migraine plus tension-type headache. 49 patients reported psychiatric disorders: migraine 10.9%, tension-type headache 12.8%, and migraine plus tension-type headache 21.4%. The MINI detected a depressive episode in 59.9, 67.0, and 69.6% of cases. Values were 18.4, 19.3, and 18.4% for anxiety, 12.7, 5.5, and 14.2%, for panic disorder and 2.3, 1.1 and 9.4% (p = 0.009) for obsessive–compulsive disorder. Multivariate analysis showed panic disorder prevailing in migraine compared with the other groups (OR 2.9; 95% CI 1.2–7.0). The association was higher (OR 6.3; 95% CI 1.4–28.5) when migraine (with or without tension-type headache) was compared to pure tension-type headache. This also applied to obsessive–compulsive disorder (OR 4.8; 95% CI 1.1–20.9) in migraine plus tension-type headache. Psychopathology of primary headache can reflect shared risk factors, pathophysiologic mechanisms, and disease burden.
doi:10.1007/s10194-010-0187-2
PMCID: PMC3452290  PMID: 20108021
Migraine; Tension-type headache; Depression; Anxiety; Prevalence
16.  Lack of association between five serotonin metabolism-related genes and medication overuse headache 
Serotonin is involved in several central nervous system functions including pain threshold, mood regulation and drug reward. Overuse of acute medications is commonly identified as a causative factor for medication overuse headache (MOH). Apparently, MOH shares with other kinds of drug addiction some common neurobiological pathways. The objective of this study is to assess the role of serotonin metabolism genes in the genetic liability to MOH. We performed a genetic association study using polymorphisms of five serotonin metabolism-related genes: serotonin transporter (5HTT), serotonin receptor 1A (5-HT1A), serotonin receptor 1B (5-HT1B), serotonin receptor 2A (5-HT2A) and serotonin receptor 6 (5HT6) genes. We compared 138 patients with MOH with a control sample of 117 individuals without headache and without drug overuse, and with 101 patients with migraine without aura but without drug overuse (MO). The genotypic and allelic distributions of all polymorphisms investigated did not differ among the three groups. In conclusion, our study does not provide evidence that the 5HTT, 5-HT1A, 5HT1B, 5HT2A and 5HT6 gene polymorphisms play a role in the genetic predisposition to MOH.
doi:10.1007/s10194-009-0168-5
PMCID: PMC3452189  PMID: 19936617
Chronic headache; Drug overuse; Medication overuse headache; Polymorphism; Serotonin; Genetic
17.  Magnetic resonance diagnostic markers in clinically sporadic prion disease: a combined brain magnetic resonance imaging and spectroscopy study 
Brain  2009;132(10):2669-2679.
The intra vitam diagnosis of prion disease is challenging and a definite diagnosis still requires neuropathological examination in non-familial cases. Magnetic resonance imaging has gained increasing importance in the diagnosis of prion disease. The aim of this study was to compare the usefulness of different magnetic resonance imaging sequences and proton magnetic resonance spectroscopy in the differential diagnosis of patients with rapidly progressive neurological signs compatible with the clinical diagnosis of sporadic prion disease. Twenty-nine consecutive patients with an initial diagnosis of possible or probable sporadic prion disease, on the basis of clinical and electroencephalography features, were recruited. The magnetic resonance protocol included axial fluid-attenuated inversion recovery-T2- and diffusion-weighted images, and proton magnetic resonance spectroscopy of the thalamus, striatum, cerebellum and occipital cortex. Based on the clinical follow-up, genetic studies and neuropathology, the final diagnosis was of prion disease in 14 patients out of 29. The percentage of correctly diagnosed cases was 86% for diffusion-weighted imaging (hyperintensity in the striatum/cerebral cortex), 86% for thalamic N-acetyl-aspartate to creatine ratio (cutoff ≤1.21), 90% for thalamic N-acetyl-aspartate to myo-inositol (mI) ratio (cutoff ≤1.05) and 86% for cerebral spinal fluid 14-3-3 protein. All the prion disease patients had N-acetyl-aspartate to creatine ratios ≤1.21 (100% sensitivity and 100% negative predictive value) and all the non-prion patients had N-acetyl-aspartate to myo-inositol ratios >1.05 (100% specificity and 100% positive predictive value). Univariate logistic regression analysis showed that the combination of thalamic N-acetyl-aspartate to creatine ratio and diffusion-weighted imaging correctly classified 93% of the patients. The combination of thalamic proton magnetic resonance spectroscopy (10 min acquisition duration) and brain diffusion-weighted imaging (2 min acquisition duration) may increase the diagnostic accuracy of the magnetic resonance scan. Both sequences should be routinely included in the clinical work-up of patients with suspected prion disease.
doi:10.1093/brain/awp210
PMCID: PMC2759338  PMID: 19755520
prion diseases; magnetic resonance; diffusion-weighted imaging; proton MR spectroscopy
18.  The “typical” migraines: genetic studies and some practical considerations 
Epidemiological genetic, family and twin studies show that the typical migraines carry a substantial genetic risk; they are currently conceptualized as complex genetic diseases. Several genetic association and linkage studies have been performed in the typical migraines. Candidate gene studies based on “a priori” pathogenic models of migraine (migraine as a calcium channelopathy; a mitochondrial DNA disorder; a disorder in the metabolism of serotonin or dopamine; in vascular risk factors or in the inflammation cascade; etc.) did not result in uniformely accepted findings. Linkage and genome wide scans gave evidence for several genetic susceptibility loci, still however in need of confirmation. Careful dissection of the clinical phenotypes and trigger factors shall greatly help future efforts in the quest for the genetic basis of the typical migraines.
doi:10.1007/s10194-003-0030-0
PMCID: PMC3452134
Migraine; Aura; Genetics; Cardiovascular risk
19.  Do changes of ANS in migraine subjects play a pathogenetic role? 
The Journal of Headache and Pain  2001;2(Suppl 1):s73-s77.
Migraine, characterized by several autonomic disturbances both during and between attacks, suggests an involvement of the autonomic nervous system (ANS). To clarify the role of the ANS in migraine pathogenesis, we reviewed the major studies on autonomic function. The results of these investigations are contradictory, suggesting hypo– and hyperfunctioning of both the sympathetic and parasympathetic nervous systems.
doi:10.1007/s101940170014
PMCID: PMC3451822
Autonomic nervous system; Migraine; Pathogenesis
20.  Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele-Specific Expression 
Human Mutation  2013;34(8):1160-1171.
ABSTRACT
Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication-based mechanisms such fork stalling and template switching or microhomology-mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele-specific LMNB1 expression levels.
doi:10.1002/humu.22348
PMCID: PMC3714349  PMID: 23649844
Lamin B1; leukodystrophy; ADLD; duplication Alu; NHEJ; FoSTeS; MMBIR

Results 1-20 (20)